Role of ephrin-A1 in lung metastasis

• Project/Area Number: 25870760
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry; Respiratory surgery
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: IEGUCHI Katsuaki 東京女子医科大学, 医学部, 助教 (90586348)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 転移 / Eph / ephrin / ADAM / がん

Outline of Final Research Achievements

It has been reported that overexpression of ephrin-A1 is positively correlated with prognosis in various cancers such as hepatocellular carcinoma. However, the detailed function remains unclear. Therefore, I focused on metastasis that get worse their prognosis in cancer patients and analyzed functions of ephrin-A1 in lung metastasis. I found that ADAM12 identified as a proteinase against ephrin-A1, cleaved ephrin-A1 in primary tumors, and the the serum level is increased. Activated EphA2 by cleaved ephrin-A1 is immediately endocytosed and undergone proteolysis and therby localization of VE-cadherin at the plasma membrane is lost. As a result of destabilization of EphA2 and VE-cadherin at the plasma membrane in lung vascular endothelial cells leads to hyper-permeability and enhances lung metastasis. A neutralizing antibody against ephrin-A1 is effective for lung metastasis. I would like to develop anti-ephrin-A1 therapeutic drugs.

Research Products

• [Journal Article] Human serum amyloid A3 (SAA3) protein, expressed as a fusion protein with SAA2, binds the oxidized low density lipoprotein receptor. (2015)
  • Author(s): Tomita T, Ieguchi K, Sawamura T, Maru Y
  • Journal Title: PLoS One Volume: 10(3) Issue: 3 Pages: e0118835-e0118835
  • DOI: 10.1371/journal.pone.0118835
  • Peer Reviewed / Open Access
• [Journal Article] LINGO-1 Protein Interacts with the p75 Neurotrophin Receptor in Intracellular Membrane Compartments (2015)
  • Author(s): Meabon JS, De Laat R, Ieguchi K, Wiley JC, Hudson MP, Bothwell M
  • Journal Title: J Biol Chem Volume: 290(15) Issue: 15 Pages: 9511-20
  • DOI: 10.1074/jbc.m114.608018
  • Peer Reviewed
• [Journal Article] ZFC3H1, a Zinc Finger Protein, Modulates IL-8 Transcription by Binding with Celastramycin A, a Potential Immune Suppressor (2014)
  • Author(s): Tomita T, Ieguchi K, Coin F, Kato Y, Kikuchi H, Oshima Y, Kurata S, Maru Y
  • Journal Title: PLoS One Volume: 30 Issue: 9 Pages: e108957-e108957
  • DOI: 10.1371/journal.pone.0108957
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ADAM12-cleaved ephrin-A1 contributes to lung metastasis. (2014)
  • Author(s): Ieguchi K, Tomita T, Omori T, Komatsu A, Deguchi A, Masuda J, Duffy SL, Coulthard MG, Boyd A, Maru Y.
  • Journal Title: Oncogene Volume: 未定 Issue: 17 Pages: 2179-90
  • DOI: 10.1038/onc.2013.180
  • Peer Reviewed / Open Access
• [Journal Article] An integrin binding-defective mutant of insulin-like growth factor-1 (R36E/R37E IGF1) acts as a dominant-negative antagonist of the IGF1 receptor (IGF1R) and suppresses tumorigenesis but still binds to IGF1R (2013)
  • Author(s): Fujita M, Ieguchi K, Cedano-Prieto DM, Fong A, Wilkerson C, Chen JQ, Wu M, Lo SH, Cheung AT, Wilson MD, Cardiff RD, Borowsky AD, Takada YK, Takada Y
  • Journal Title: Journal of Biological Chemistry Volume: 288 Issue: 27 Pages: 19593-19603
  • DOI: 10.1074/jbc.m113.470872
  • Peer Reviewed
• [Journal Article] Ephrin-A1 expression induced by S100A8 is mediated by the toll-like receptor 4 (2013)
  • Author(s): Ieguchi K, Omori T, Komatsu A, Tomita T, Deguchi A, Maru Y
  • Journal Title: Biochem Biophys Res Commun Volume: 440(4) Issue: 4 Pages: 623-629
  • DOI: 10.1016/j.bbrc.2013.09.119
  • Peer Reviewed
• [Presentation] Role of the sympathetic nervous system in lung metastasis (2015)
  • Author(s): Ieguchi K, Maru Y
  • Organizer: 2nd International symposium 2015 “Neuro-Vascular wiring”
  • Place of Presentation: 関西セミナーハウス（京都府・左京区）
  • Year and Date: 2015-01-18 – 2015-01-19
• [Presentation] Breakdown of the Eph/ephrin system in vascular endothelial cells causes lung metastasis (2014)
  • Author(s): Ieguchi K, Tomita , Maru Y
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: 京都市勧業館みやこめっせ（京都府・左京区）
  • Year and Date: 2014-04-16
• [Presentation] ADAM12-cleaved ephrin-A1 contributes to lung metastasis (2013)
  • Author(s): Ieguchi Katsuaki, Tomita Takeshi, Yoshiro Maru
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Book] 血液内科 (2014)
  • Author(s): 家口勝昭、丸義朗
  • Total Pages: 7
  • Publisher: 科学評論社
• [Remarks] 東京女子医科大学 研究業績データベース
  • URL: http://gyoseki.twmu.ac.jp/twmhp/KgApp?kyoinId=ymdmgiykggi
• [Remarks] 東京女子医科大学 薬理学教室
  • URL: http://www.twmu.ac.jp/Basic/yakuri/index.html